Bosentan Monohydrate, the active ingredient in the drug product Tracleer®, is an endothelin receptor antagonist, belonging to a class of highly substituted pyrimidine derivatives, which has the chemical name 4-tert-butyl-N-[6-(2-hydroxy-ethoxy)-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide monohydrate and the following structural formula (I):

Bosentan Monohydrate was developed for treatment of pulmonary arterial hypertension.
Hoffmann La-Roche EP 526708 discloses the preparation of crude Bosentan sodium salt, which involves coupling of 4-tert-butyl-N-[6-chloro-5-(2-methoxy-phenoxy)-2-(2-pyrimidinyl)-pyrimidin-4-yl]-benzenesulfonamide and sodium ethylene glycolate in ethylene glycol as a solvent at a temperature of 100° C.
The formation of the dimer impurity of formula (Ia) and of the pyrimidinone impurity of formula (Ib)
is a known drawback of the so called first-generation process (see Harrington et. al., Organic Process Research & Development 2002, Vol. 6, 120-124).
The control of impurities is currently a critical issue to the drug manufacturer, who is required by the regulatory authorities to include in the submission of a marketing authorization for a drug product, analytical data which demonstrate that impurities are absent from the active pharmaceutical ingredient (API) at the time of manufacture, or are present at acceptable levels.
Therefore, the formation of any impurities and particularly, in the present case, the formation of the above-identified dimer and pyrimidinone impurities, requires costly and laborious separation steps to isolate a pharmaceutically suitable Bosentan Monohydrate. For example, according to the above-cited Harrington's article, at least two final product crystallizations from methanol-isopropyl acetate are required to lower said impurities levels.
In order to avoid the formation of the undesired dimer impurity, in Hoffmann La-Roche EP 1254121 a variation of the final step was performed by using, instead of sodium ethylene glycol, a mono-protected ethylene glycol, such as (mono) tert-butyl ether protected ethylene glycol. After coupling tert-butyl ether protected ethylene glycol with the 6-chloro sulfonamide intermediate, tert-butyl group is hydrolyzed with formic acid to obtain a formyl derivative, which is removed with sodium hydroxide (NaOH) to yield Bosentan.
As follows from the above mentioned prior art, there is a need for a process to prepare Bosentan Monohydrate in a pure form by an effective method, which is applicable to large-scale industrial production.